We have continued this study by 1) measuring autologous serum for CD4 blocking activity on autologous virus, by 2) analyzing serum from chimps immunized and infected with HIV, and by 3) studying the effect of CD4-blocking antibodies on monotropic HIV strains. To analyze autologous serum-virus interactions, we have tested serum from the labworker infected with IIIB and have found that, on cell-associated CD4 binding assays, this individual has the highest blocking activity against IIIB of any serum yet tested, but has only weak cross reactivity on the other laboratory strains used in the blocking assays in contrast to most other sera. Surprisingly, this serum although containing high concentrations of antibody to gpl20 in the ELISA assay, has no ELISA CD4-gpl20 blocking activity. Analysis of immunized and HIV infected chimp sera, in contrast to the human sera, has found that HIV envelope immunized chimp sera contain high levels of blocking antibodies to rgpl20 in the ELISA format but have no cell-associated CD4 blocking activity. These results demonstrate that dramatic differences exist between the conformation of gpl20 when in solution (or on the ELISA plate) and when it is associated with gp4l on the cell surface or virus membrane. The results also show that the immune response to envelope differs greatly depending on the form in which envelope is presented to the immune system. These studies have been extended into an analysis of primary, monotropic and chimeric virus isolates. These isolates have shown a dramatic resistance to neutralizing antibodies which appears to involve resistance both to antibodies directed to the CD4 binding site as well as to the V3 neutralizing domain. Our studies provide new insight into role of antibodies directed towards the CD4 site on envelope in protective immunity and provide the foundation for vaccine and therapeutic approaches directed at this epitope.